Mouse Study Shows That Ketamine Metabolite May Treat Depression with Fewer Side Effects

The drug ketamine has been used intravenously for years to rapidly treat depression, because it can take effect within hours. Unfortunately, its antidepressant effects fade in 3–5 days, and it has some unpleasant side effects. In larger doses ketamine is used as an anesthetic and sometimes as a club drug, for its ability to induce hallucinations and dissociation. It can be addictive as well.

A 2016 animal study by Todd Gould and colleagues published in the journal Nature identified a byproduct of ketamine that may be able to provide the drug’s benefits without its side effects.

When the body breaks down ketamine, it produces several chemicals that are known as ketamine metabolites. The researchers found that one of these, called hydroxynorketamine, reversed a depression-like state in mice, without producing the side effects that would be expected of ketamine.

Gould and colleagues also determined that blocking the transformation of ketamine into hydroxynorketamine prevented ketamine’s antidepressant effects.

Ketamine’s unpleasant anesthetic and dissociative effects result from the blockade of a particular receptor for the neurotransmitter glutamate (the NMDA glutamate receptor). Researchers originally thought that the NMDA blockade was linked to ketamine’s antidepressant effects, but this appears not to be the case. Instead, hydroxynorketamine seems to activate a different type of glutamate receptor, the AMPA receptor.

Gould and colleagues plan to test hydroxynorketamine in humans soon. Because it has already been present in the human body following ketamine administration, they expect it to be safe.

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